title: Synthesis and biological evaluation of a new series of highly functionalized 7'-homo-anhydrovinblastine derivatives.
abstract: Sixteen new 7'-homo-anhydrovinblastine derivatives were prepared in one or two steps from vinorelbine by means of an original and regiospecific rearrangement and subsequent diastereoselective reduction. This strategy has allowed fast access to a family of vinca alkaloid derivatives with an enlarged and functionalized ring C'. Their synthesis and biological evaluation are reported. One compound (compound 35) is 1.7 times more active than vinorelbine as a tubulin assembly inhibitor. Moreover, some of these compounds are highly cytotoxic, and two of them are more potent than vinorelbine on HCT116 and K562 cell lines. Molecular modeling studies, carried out with two of the new vinca derivatives, provide useful hints about how a given functionalization introduced at positions 7' and 8' of the C' ring results in improved binding interactions between one of the new derivatives and the interdimer interface when compared to the parent compound vinblastine.
authors.affiliation: Centre de Recherche de Gif, Institut de Chimie des Substances Naturelles, UPR 2301 du CNRS, LabEx Lermit, Avenue de la Terrasse, 91198 Gif-sur-Yvette Cedex, France.
authors.forename: Olga
authors.initials: O
authors.lastname: Gherbovet
authors.forename: Claire
authors.initials: C
authors.lastname: Coderch
authors.forename: María Concepción
authors.initials: MC
authors.lastname: García Alvarez
authors.forename: Jérôme
authors.initials: J
authors.lastname: Bignon
authors.forename: Sylviane
authors.initials: S
authors.lastname: Thoret
authors.forename: Marie-Thèrese
authors.initials: MT
authors.lastname: Martin
authors.forename: Françoise
authors.initials: F
authors.lastname: Guéritte
authors.forename: Federico
authors.initials: F
authors.lastname: Gago
authors.forename: Fanny
authors.initials: F
authors.lastname: Roussi
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D008870:Microtubules / Q000737:chemistry; D008958:Models, Molecular; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D050257:Tubulin Modulators / Q000138:chemical synthesis* / Q000494:pharmacology; D014747:Vinblastine / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; D050257:Tubulin Modulators; D014747:Vinblastine